Ketotricyclo[5.2.1.0]decane derivatives

ABSTRACT

The invention relates to ketotricyclo[5.2.1.0]-decane derivatives of the formula I                    
     wherein 
     Phe is a phenyl group which is unsubstituted or substituted by 1 to 5 hydroxyl, alkyl or alkoxy groups having 1 to 10 C atoms, 
     and their preparation and use as UV filters, in particular in cosmetic or pharmaceutical formulations.

This application is a 371 of PCT/EP93/00234 filed on Feb. 2, 1993.

The invention relates to ketotricyclo[5.2.1.0]-decane derivatives of theformula I

wherein

Phe is a phenyl group which is unsubstituted or substituted by 1 to 5hydroxyl, alkyl or alkoxy groups having 1 to 10 C atoms,

and to a process for their preparation and their use in cosmeticformulations, in particular for protection from solar radiation, and inpharmaceutical formulations for preventive treatment of inflammationsand allergies of the skin or certain types of cancer.

As is known, the skin reacts sensitively to the sun's rays, which cancause common sunburn or erythema, and also more or less severe burns.

However, the sun's rays also have other adverse effects: they cause theskin to lose its elasticity and develop wrinkles and thus lead topremature ageing. Dermatoses can also sometimes be observed. In theextreme case, skin cancer occurs in some people.

It is also desirable to protect hair from photo-chemical damage, inorder to prevent changes in color shades, bleaching or damage of amechanical nature.

It is known that the components contained in cosmetic preparations arenot always sufficiently stable to light and decompose under the actionof light rays.

As is known, ultraviolet rays with a wavelength of less than 400 nm formthe most dangerous part of the sun's rays. It is also known that becauseof the presence of the ozone layer of the earth's atmosphere, whichabsorbs some of the solar radiation, the lower limit of the ultravioletrays which reach the earth's surface is about 280 nm.

It thus appears desirable to provide compounds which can absorb UV raysin a wavelength range of 280 to 400 nm, that is to say also UV-B rayswith a wavelength of between 280 and 320 nm, which form a decisive rolein the development of solar erythema, and also UV-A rays with awavelength between 320 and 400 nm, which tan the skin but also age it,promote initiation of an erythematous reaction or intensify thisreaction in certain people or can even induce phototoxic orphotoallergic reactions.

The sunscreen filters nowadays customary in cosmetics are classifiedinto UVA and UVB filters. While there are good filters in the UVB range(280-320 nm) with substances such as Eusolex® 6300 or Eusolex® 232,those used in the UVA range (320-400 nm) present problems.

Dibenzoylmethanes, such as Parsol® 1789 or Eusolex® 8020, do not have anunlimited stability when exposed to UV irradiation, which on the onehand reduces the effectiveness of the filter in the course of time andon the other hand can promote photosensitizations of the skin inisolated cases. The benzophenones also used as UVA filters have only alimited solubility in the oils used in cosmetics, and they have arelatively low absorption. On the other hand, only a few water-solubleUVA filters are currently known, but their UV absorption is low.

Similar benzylidenecamphor derivatives are known, for. example, from EP0 390 682; however, these do not have a tricyclodecanone structure.

A compound with the designation(+−)-6-oxobenzylidene(3arH.7acH)-5hexahydro-4t.7t-methanoindane, whichis embraced by formula I when Phe is unsubstituted phenyl is cited inBeilstein under number BRN=3196309.

Comparison with the original literature cited (H. A. Bruson, T. W.Riener, J. Am. Chem. Soc 67, 1945, 723-28), shows, however, that it isnot the 9-benzylidene-tricyclo[5.2.1.0^(2,6)]decan-8-one, according tothe invention but 3-benzylidenetricyclo[3.3.2.^(1,4)0^(1,5)]decan-2-one.

It has been found that ketotricyclo[5.2.1.0]-decane derivatives of theformula I wherein Phe is a phenyl group which is unsubstituted orsubstituted by 1 to 5 hydroxyl, alkyl or alkoxy groups, in particular anunsubstituted phenyl group, have outstanding UVB filter properties.Their solubility in the oils used in cosmetics is very good, so that useconcentrations of up to at least 10% of the formulation are possibleeven in complicated formulations.

The compounds according to the invention furthermore have an exceptionalphotostability to UV radiation which by far exceeds the stability of UVfilter substances known to date, and are particularly suitable as UVB orUV broad-band filters.

If the extinction in the UVA range has a minimum, this is not adisadvantage, since a UVA filter can be co-incorporated into theformulation without problems.

The compounds of the formula I furthermore can also be used forpreventive treatment of inflammations and allergies of the skin and forprevention of certain types of cancer.

In addition to their good properties as filters, the compounds accordingto the invention are distinguished by a good heat and photochemicalstability.

These compounds furthermore offer the advantage of not being toxic orirritating and of being completely harmless to the skin.

They are distributed uniformly in the conventional cosmetic carriers,and can form a continuous film, in particular in fat carriers; they canbe applied to the skin in this manner, in order to form an effectiveprotective film.

The invention relates to the compounds of the abovementioned formula I,in particular wherein Phe is unsubstituted phenyl or 1,4-phenyl which issubstituted by 1 or 2 alkoxy groups having 1 or 2 C atoms.

Phe is preferably a group of the formula

In this formula, R is a methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, t-butyl or 1,1,3,3-tetra-methylbutyl radical, a methoxy, ethoxyor 2-ethylhexyloxy radical or hydrogen, preferably hydrogen.

n is 1 to 5, preferably 1 or 2.

The phenyl group is preferably unsubstituted or substituted by one ortwo alkoxy groups having 1 to 8 C atoms, in particular by methoxy,ethoxy or 2-ethylhexyloxy groups.

Preferred compounds of the formula I are those of the formulae I1 to I8,wherein A is a group of the formula

and

R is alkyl or alkoxy having 1 to 10 C atoms.

The compounds of the formula I are obtained, for example, by a processin which a benzaldehyde derivative of the formula II

Phe—CHO  II

wherein Phe has the meaning given, is reacted with8-ketotricyclo[5.2.1.0^(2,6)] decane in the presence of a base.

The reaction is as a rule carried out in an inert diluent, preferably aprotic solvent, in particular an alcohol, such as, for example,methanol, ethanol, isopropanol or tert-butanol, or an aprotic solvent,such as diethyl ether, toluene or cyclohexane, or mixtures of thesolvents mentioned. Alkali metal alcoholates, such as, for example,sodium methylate, sodium ethylate or potassium tert-butylate, arepreferably employed as the base.

The reaction can be carried out at temperatures between 0° C. and theboiling point of the reaction mixture, and is preferably carried out at25 to 60° C.

The aldehydes of the formula II are known or are prepared by knownmethods.

8-Ketotricyclo[5.2.1.0^(2,6)] decane is known and is commerciallyobtainable as an isomer mixture.

The invention also relates to the process for the preparation of the newcompounds of the formula I.

The invention furthermore relates to a cosmetic formulation whichcomprises an active amount of at least one derivative of the aboveformula I in a cosmetically compatible carrier.

The cosmetic agent according to the invention can be used as an agentfor protecting the human epidermis or the hair or as a sunscreen agent.

The invention furthermore relates to a process for protecting the skinand natural or sensitized hair from the sun's rays, an active amount ofat least one compound of the formula I being applied to the skin orhair.

“Sensitized hair” means hair which has been subjected to a permanentwave treatment or a dyeing or bleaching process.

The invention furthermore relates to a colored or non-coloredlight-stabilized cosmetic formulation which comprises an active amountof at least one benzylidene-camphor derivative of the above formula I.

If the cosmetic agent according to the invention is used as an agent forprotecting the human epidermis from UV rays, it is present in variousforms which are usually used for this type. It can thus be, inparticular, in the form of oily or oily-alcoholic lotions, emulsions,for instance as a cream or milk in the form of oily-alcoholic,oily-aqueous or aqueous-alcoholic gels, or as solid sticks, or can bemade up as an aerosol.

It can comprise cosmetic adjuvants which are usually used in this typeof agent, such as, for example, thickening agents, softening agents,moistening agents, surface-active agents, preservatives, agents whichprevent foam formation, perfumes, waxes, lanolin, propellents, dyestuffsand/or pigments, which color the agent itself or the skin, and otheringredients usually used in cosmetics.

The compound of the formula I is as a rule contained in an amount of 0.5to 10%, preferably 1 to 8%, in particular 1 to 5%, based on the totalweight of the cosmetic agent for protection of the human epidermis.

An oil, wax or other fatty substance, a lower monoalcohol or a lowerpolyol or mixtures thereof can be used as solubilizing agents. Theparticularly preferred monoalcohols or polyols include ethanol,i-propanol, propylene glycol, glycerol and sorbitol.

A preferred embodiment of the invention is an emulsion which is in theform of a protective cream or milk and comprises, in addition to thecompound of the formula I, fatty alcohols, fatty acid esters, inparticular triglycerides of fatty acids, fatty acids, lanolin, naturallyoccurring or synthetic oils or waxes and emulsifiers in the presence ofwater.

Other preferred embodiments are oily lotions based on naturallyoccurring or synthetic oils and waxes, lanolin, fatty acid esters, inparticular triglycerides of fatty acids, or oily-alcoholic lotions basedon a lower alcohol, such as ethanol, or on a glycol, such as propyleneglycol, and/or on a polyol, such as glycerol, and oils, waxes and fattyacid esters, such as triglycerides of fatty acids.

The cosmetic agent according to the invention can also be in the form ofan alcoholic gel which comprises one or more lower alcohols or polyols,such as ethanol, propylene glycol or glycerol, and a thickening agent,such as silica. The oily-alcoholic gels furthermore comprise naturallyoccurring or synthetic oil or wax.

The solid sticks comprise naturally occurring or synthetic waxes andoils, fatty alcohols, fatty acid esters, lanolin and other fattysubstances.

The invention also relates to cosmetic sunscreen agents which compriseat least one compound of the formula I and can comprise other UVB and/orUVA filters.

In this case, the amount of filter of the formula I is as a rule between1.0 and 8.0% by weight, based on the total weight of the sunscreenagents.

If an agent is made up as an aerosol, the customary propellents, such asalkanes, fluoroalkanes and chlorofluoroalkanes, are used as a rule.

If the agent according to the invention is to protect natural orsensitized hair from UV rays, it can be in the form of a shampoo,lotion, gel or emulsion for rinsing out, the particular formulationbeing applied before or after shampooing, before or after dyeing orbleaching or before or after a permanent wave; alternatively, the agentis in the form of a lotion or gel for styling and treatment, in the formof a lotion or gel for brushing or setting a waterwave, or in the formof a hair lacquer, permanent wave agent or dyeing or bleaching agent forhair. In addition to the compound according to the invention, this agentcan comprise various adjuvants used in this type of agent, such assurface-active agents, thickening agents, polymers, softening agents,preservatives, foam stabilizers, electrolytes, organic solvents,silicone derivatives, oils, waxes, antiseborrhoeic agents, dyestuffsand/or pigments which color the agent itself or the hair, or otheringredients usually used for hair care. The agent as a rule comprises1.0 to 5.0% by weight of the compound of the formula I.

The present invention also relates to cosmetic agents which comprise atleast one compound of the formula I as agents for protection from UVrays and as antioxidizing agents; these agents include hair products,such as hair lacquers, waterwave lotions for setting the hair, ifappropriate for treatment or gentler styling, shampoos, coloringshampoos, hair coloring agents, make-up products, such as nail varnish,creams and oils for skin treatment, foundation, lipsticks, skin careagents, such as bath oils or creams, and other cosmetic agents which cancause problems with light stability and/or oxidation in the course ofstorage with respect to their components. Such agents as a rule comprise1.0 to 5.0% by weight of a compound of the formula I.

The invention furthermore relates to a process for protection ofcosmetic agents from UV rays and oxidation, an active amount of at leastone compound of the formula I being added to these agents.

The invention furthermore relates to the use of the compounds of theformula I as sun filters having a wide absorption span in a wavelengthrange of 320 to 400 nm.

The invention furthermore relates to the use of the compounds of theformula I as cosmetic products.

As already mentioned above, in the course of its studies, the ApplicantCompany furthermore has found that the compounds of the formula I have asignificant pharmacological activity in the field of preventivetreatment of inflammations and skin allergies.

The invention also relates to the compounds of the formula I for use asa medicament.

The invention furthermore relates to a pharmaceutical agent whichcomprises an active amount of at least one compound of the formula I asthe active substance in a non-toxic carrier or excipient.

The pharmaceutical agent according to the invention can be administeredorally or topically.

For oral administration, the pharmaceutical agent is present in the formof pastels, gelatin capsules or coated tablets or as a syrup,suspension, solution, emulsion and the like. For topical application, itis present in the form of an ointment, cream, pomade, solution, lotion,gel, spray, suspension and the like.

This agent can comprise inert or pharmacodynamically active additives,in particular hydrating agents, antibiotics, steroid or non-steroidantiinflammatory agents, carotinoids and agents against psoriasis.

This agent can also comprise flavor-improving agents, preservatives,stabilizers, moisture regulators, pH regulators, modifiers for osmoticpressure, emulsifiers, local anaesthetics, buffers and the like.

It can furthermore be conditioned in a manner which is known per se in aretarded form or in a form in which the active compound is releasedrapidly.

Even without further statements, it is assumed that an expert canutilize the above description in the broadest scope. The preferredembodiments are therefore to be interpreted merely as a descriptivedisclosure and in no way as a disclosure which is limited in any manner.

The complete disclosure of all the applications, patents andpublications mentioned above and below and the corresponding ApplicationP 42 04 922, filed on 19.02.1992, are introduced into this Applicationby reference.

The following examples are representative of the present invention.

EXAMPLE 1 9-Benzylidene-8-keto-tricyclo-[5.2.1.0^(2,6)] decane

A suspension of 40 mmol (6.3 g) of 8-ketotricyclo[5.2.1.0^(2,6)] decane(isomer mixture) and 60 mmol of sodium methylate (10.7 g of a 30%strength solution) in 75 ml of cyclohexane is stirred at 50° C. for 30′.50 mmol (5.3 g) of benzaldehyde are then added dropwise and the mixtureis heated at reflux for 1 hour. Thereafter, the mixture is cooled toroom temperature and 175 ml of water are added. The phases are separatedand the aqueous phase is extracted with cyclohexane. The combinedorganic extracts are extracted by shaking with 50 ml of 1N HCl solution,washed neutral with water, dried, filtered and evaporated on a rotaryevaporator.

Chromatography with toluene/ethyl acetate 98:2 gave a crude product,which was recrystallized from isopropanol for further purification.

5.94 g=62%;

Melting point: 87.7-88.1° C.

UV (ethanol, c=1 mg/100 ml):2 [sic]_(max)=305 nm;

E=0.946 (d=1 cm);

log ε=3.60.

The other spectra correspond to the expected compound.

The following are prepared analogously:

R Solvent Max (nm) Extinction logε UV 2,3-OCH₃ EtOH 293.2 0.591 3.30 B2,4-OCH₃ EtOH 337.3 0.661 3.35 AB 2,5-OCH₃ EtOH 353.6 0.269 2.95 A3,4-OCH₃ EtOH 329.6 0.675 3.35 AB 2,4,6-OCH₃ EtOH 326.2 0.528 3.21 AB2,4,5-OCH₃ EtOH 359.5 0.491 3.18 A 2,3,4-OCH₃ EtOH 320.0 0.653 3.30 AB

Solubility of the substances according to the invention

R, R′ Isopropanol Miglyol Paraffin oil Water H, H 7.40% 10.80% 2.40%0.01% 2,3-OCH₃ 8.57% 9.64% 0.91% 0.01% 2,4-OCH₃ 0.95% 1.64% 0.14% 0.01%3,4-OCH₃ 1.57% 3.19% 0.17% 0.01% 2,4,6-OCH₃ 0.26% 0.43% 0.02% 0.01%2,4,5-OCH₃ 0.04% 0.07% 0.03% 0.01% 2,3,4-OCH₃ 3.21% 2.64% 0.26% 0.01%

Photostability of the substances according to the invention

Loss of extinction at λ_(max) after irradiation [minutes]

R, R′ 15 min. 30 min. 60 min. 120 min. 180 min. H, H 10.00% 10.00%12.50% 17.50% 22.50% 2,3-OCH₃ 12.50% 12.50% 14.10% 17.20% 18.80%2,4-OCH₃ 13.60%  22.0% 37.30% 59.30% 76.30% 3,4-OCH₃ 17.50% 26.30%42.10% 64.90% 80.70% 2,4,6-OCH₃ 28.80% 33.80% 2,4,5-OCH₃ 24.40% 61.50%2,3,4-OCH₃ 30.70% 61.30%

EXAMPLE 2 Sunscreen Cream (water-in-oil)

% A 9-Benzylidene-8-ketotricyclo- (1) 3.00 [5.2.1.0^(2,6)) decane(=BKTD) Arlacel 581 (2) 7.00 Highly liquid paraffin (1) 6.00 (Art. No.7174) Arlamol S 7 (2) 2.00 Lunacera M (3) 5.00 Dow Corning 344 (4) 4.00Miglyol 812 (5) 2.00 Oxynex 2004 (Art. No. 6940) (1) 0.05 B Glycerol(Art. No. 4093) (1) 2.00 Magnesium sulphate heptahydrate (1) 0.17 (Art.No. 5882) Preservative q.s. Water, demineralized to 100.00

Preparation

Heat phase A to 75° C. and phase B to 80° C. Stir phase B slowly intophase A. Homogenize. Cool, while stirring. If appropriate, perfume at40° C.

Sources of supply:

(1) E. Merck, Darmstadt

(2) ICI, Essen

(3) LW Fuller, Lüneburg

(4) Dow Corning, Düsseldorf

(5) Hüls Troisdorf AG, Witten

EXAMPLE 3 Sunscreen Cream (oil-in-water)

% A BKTD (1) 3.00 Emulsifier E 2155 (2) 8.00 Stearic acid (Art. No. 671)(1) 2.00 Liquid paraffin (1) 6.00 (Art. No. 7162) Non-caking paraffin(1) 6.00 (Art. No. 7158) Cetyl alcohol (Art. No. 989) (1) 2.50 Miglyol812 (3) 9.50 Abil AV 200 (2) 0.50 Cetyl palmitate (Art. No. 15419) (1)5.50 Tocopherol acetate (1) 0.05 (Art. No. 500952) B Glycerol (Art No.4093) (1) 3.00 Propane-1,2-diol (Art. No. 7478) (1) 2.00 Karion F liquid(Art. No. 2993) (1) 5.00 Allantoin (Art. No. 1015) (1) 0.25Triethanolamine (Art. No. 8377) (1) 0.50 Preservative q.s. Water,demineralized to 100.00

Preparation

Heat phase A to 75° C. and phase B to 80° C. Stir phase B slowly intophase A. Homogenize. Cool, while stirring. If appropriate, perfume at40° C.

Sources of supply:

(1) E. Merck, Darmstadt

(2) Th. Goldschmidt, Essen

(3) Hüls Troisdorf AG, Witten

EXAMPLE 4 Sunscreen Milk (water-in-oil)

% A BKTD (1) 3.00 Pionier L-15 (2) 19.00 Viscous paraffin (Art. No.7160) (1) 15.00 B Glycerol (Art. No. 4093) (1) 5.00 Magnesium sulfateheptahydrate (1) 0.50 (Art. No. 5882) Preservative q.s. Water,demineralized to 100.00

Preparation

Heat phase A to 75° C. and phase B to 80° C. Stir phase B slowly intophase A. Homogenize. Cool, while stirring. If appropriate perfume at 40°C.

Sources of supply:

(1) E. Merck, Darmstadt

(2) Hansen & Rosenthal, Hamburg

EXAMPLE 5 Sunscreen Milk (water-in-oil)

% A BKTD (1) 3.00 Eumulgin B 1 (2) 3.00 Cutina MD (2) 8.00 Miglyol 812(3) 7.00 B Glycerol (Art. No. 4093) (1) 5.00 Preservative q.s. Water,demineralized to 100.00

Preparation

Heat phase A to 75° C. and phase B to 80° C. Stir phase B slowly intophase A. Homogenize. Cool, while stirring. If appropriate, perfume at40° C.

Sources of supply:

(1) E. Merck, Darmstadt

(2) Henkel, Düsseldorf

(3) Hüls Troisdorf AG, Witten

EXAMPLE 6 Sunscreen Oil

% A BKTD (1) 3.00 Arlatone T (2) 2.00 Miglyol 812 (3) 16.00 Cetiol B (4)22.50 Isopropylmyristate (4) 7.50 Highly liquid paraffin (1) 48.85 (Art.No. 4174[sic]) Oxynex 2004 (Art. No. 6940) (1) 0.05 b Perfume oil 72979(5) 0.10

Preparation

Heat phase A to 70° C., while stirring, until all the components havedissolved, stir until cold and add phase B at 40° C.

Sources of supply:

(1) E. Merck, Darmstadt

(2) ICI, Essen

(3) Hüls Troisdorf AG, Witten

(4) Henkel, Düsseldorf

(5) Haarmann & Reimer, Holzminden

What is claimed is:
 1. A ketotricyclo[5.2.1.0]decane derivative offormula I

wherein Phe is a phenyl group which is unsubstituted or substituted by 1to 5 alkyl or alkoxy groups having 1 to 10 C atoms.
 2. Ketotricyclo[5.2.1.]decane derivatives according to claim 1, wherein Phe is a phenylgroup which is unsubstituted or substituted by 1 or 2 alkoxy groupshaving 1 or 2 C atoms.
 3. A method for preventing inflammations andallergies of the skin caused by UV irradiation, comprising administeringan effective amount of a compound of claim
 1. 4. A method of preventingcancer caused by UV irradiation, comprising administering an effectiveamount of a compound of claim
 1. 5. A process for the preparation of aketotricyclo[5.2.1.0]decane derivative of claim 1, comprising reacting abenzaldehyde compound of formula II Phe—CHO  II wherein Phe has thegiven meaning, with 8-ketotricyclo[5.2.1.0^(2,6)]decane in the presenceof a base.
 6. A process according to claim 5, wherein the base is analkali metal alcoholate.
 7. A cosmetic formulation, comprising aneffective UV radiation-protective amount of aketotricyclo[5.2.1.0]decane derivative of claim 1 in a cosmeticallycompatible carrier.
 8. A cosmetic for mulation of claim 7, wherein theketotricyclo[5.2.1.0]decane derivative is present in an amount of 0.5 to10% by weight of the formulation.
 9. A cosmetic formulation of claim 7,further comprising a UV-A filter.
 10. A pharmaceutical preparation,comprising an effective UV radiation-protective amount of aketotricyclo[5.2.1.0]decane derivative of claim 1 and a pharmaceuticallyacceptable excipient.
 11. A pharmaceutical preparation of claim 10, fortopical use.